Project 1 is focused on understanding how virus and host control innate immune defenses and the outcome of West Nile (WNV) virus infection. West Nile virus is a model flavivirus. Its replication program, host immune induction, and innate immune evasion strategies, are representative of other members of the flavivirus family. WNV is emerging in the Western hemisphere, and is now a contemporary public health threat. Our studies have defined specific pathogen recognition (PRR) pathways and interferon regulatory factors (IRFs) as key features of immune triggering and programming during WNV infection. We hypothesize that viral triggering and control of PRR signaling programs and innate immune defenses of the host cell defines the tissue tropism and virulence properties of WNV infection. To investigate this hypothesis we will conduct in vitro and in vivo studies to 1) Define the cell-specific PRR pathways that trigger innate immunity against WNV infection; 2) Identify the interferon-stimulated innate immune effector genes that control WNV replication, and 3) Determine the molecular mechanisms by which pathogenic WNV evades the innate immune actions of alpha/beta interferons. In collaboration with Projects 2-5 and the Virology Core, we will define the role of the innate immune response in governing immunity and the outcome of WNV infection. These studies will define the virus/host interface of WNV infection that controls immunity, and will provide novel insights to guide vaccine and therapeutic strategies aimed at modulating WNV and flavivirus infection.